APPROPRIATE ANTISEIZURE MEDICATION SELECTION

Dr. Nayyereh Akbari

OUTLINES

Approach to first seizure

Who need prolonged AEDSystematic approach

Seizure type

Epilepsy type Epileptic syndrome

Etiology

Comorbid conditions…

SYSTEMATIC APPROACH

Individual with new-onset seizure

Is event suggestive of seizure Migraine, TIA, Syncope…

Fever , FND, Mental status change

Urgent evaluation for acute symptomatic seizure

Provoking factor Unprovoked seizureNonurgent evaluation of provoked seizure

Perform EEG and epilepsy protocol MRI

Are the test are consistent with epilepsy etiology

Choose first line AED

First unprovoked seizure

FIRST STEP

Mimickers

Acute symptomatic: temporary ASM/AED

Provoked seizure: counseled about lifestyle modification

Unprovoked seizure

WHO NEEDS PROLONGED AED ADMINISTRATION?

Epilepsy definition: At least two unprovoked or reflex seizures (24 hours apart) One unprovoked or reflex seizure + 60 % risk of recurrence in the next 10 years: Epileptogenic structural abnormality interictal epileptiform activity Nocturnal convulsion

SEIZURE TYPE

SEIZURE FREEDOM RATE FOLLOWING AED ADMINISTRATION

50%

13%4%

33%

seizure freedom with firstdrug: 50%seizure freedom with seconddrug:13%seizure freedom with thirddrug:4:drug resistant epilesy:33%

Broad spectrum AED Narrow spectrum

Valproate Carbamazepine

Topiramate Eslicarbazepine

Lamotrigine Oxcarbazepine

Levetiracetam Gabapantine

Brivaracetam Pregabaline

Phenobarbital Lacosomide

Primidone Ethosuximide

Clobazam Phenytoin

Clonazepam Ezogabine

Zonisamaide Vigabatrine

Rufinamide Tiagabine

Felebemate

Perampanel

POLYTHERAPY

Adding a second AED or switching to other ?

Avoid

drug-drug interaction especially about EIAED or VPA

drug with similar anti seizure mechanism

drug with similar side effect

Drug resistant epilepsy is defined as failure to achieve seizure freedom after adequate trial of two appropriate AED in monotherapy or combination.

ROLE OF SEIZURE TYPES

1- GTCS: Different broad spectrum drug should be used.

2- Absence: VPA= ETU>LTG

3- Myoclonic jerks: LEV, VPA, Clonazepam

ROLE OF EPILEPSY TYPES

1- Idiopathic generalized epilepsy: Three types of seizures including GTCS, myoclonic jerks and absence should be covered.

2- Focal epilepsy: Narrow or broad spectrum drugs could be used based on patient’s age and comorbid condition.

3- Epileptic encephalopathy: The appropriate anti-seizure medication should be selected based on specific epilepsy syndrome .precision medicine could be helpful.

EPILEPTIC ENCEPHALOPATHY

There are vast majority of different epileptic encephalopathy syndromes which drug selection should be based on specific epilepsy syndromes. Some examples:

- Dravet’s syndrome: SCN1A mutation: Na-channel blockers should be avoided

SCN2A or 8A mutation: Best choices: Na-channel blockers.

- ESES : BNZ and steroid

GRIN2A mutation: Memantine(NMDA antagonist)

- LGS: Broad spectrum AEDs should be selected based on seizure types.

LENNOX- GASTAUT SYNDROME

Seizure types: GTCS, atypical absence, atonic, tonic, myoclonic

Epilepsy type: mixed generalized and focal epilepsy

Narrow spectrum drugs and sedatives should be avoided.

GTCS: VPA, LTG, TPM

Atonic: VPA, Clobazam, Rufinamide

Atypical absence: VPA, ETU, LTG

LGSKetogenic diet

Resective surgery

VNS

callosotomy

VPA

LTG(adjunctive)

RFMTry to discontinue

previous drug

Subsequent adjunctive therapies

TPM CLB FBM

Limited evidence:LEV,ZNS,PEREthosuximide for absence,

Phenobarbital for GTCbanzodiazpin, stroid, stripentol,

cannabidiol

May worsen drop attack:Carbamazepine,

Oxcarbazepine,Eslicarbazepin,Phenytoin,Tiagabine

ROLE OF COMORBID CONDITIONS

Age with special consideration to elderly

Sex with special consideration to women of childbearing age

Body Mass Index

Comorbid mood and other psychiatric disorder

Co-morbid medical conditions

Bone health

Drug-Drug interaction

Skin rash

ELDERLY CONCERNS

Drug metabolism may lower significantly during elderly, more than 20% for lacosomide,lamotrigine,levetiracetam,Topiramate,oxcarbazepine, felbamate, gabapantine and pregabaline.

slower titration and lower maintenance doses should be selected.

Bone health is a concern in elderly.

Comorbid medical and psychiatric conditions :drug interaction should be keep in mind.

Try: Levetiracetam, Lamotrigine, Lacosomide

ROLE OF SEX

Women in childbearing age

o Oral contraceptive pill

o Teratogenic effect of AED

o Breast feeding

Effect on contraceptive AED

Failure Carbamazepine, Eslicarbazepine , Phenobarbital, Phenytoin, Primidone,Clobazam, Rufinamide

Failure at high dose Topiramate, Felbamate, Perampanel

No known effect Valproate, Lacosomide, Lamotrigine,Levetiracetam,Clonazepam,ZonisamideEtosuximide, Gabapantine, Ezogabin,Tiagabin, Vigabatrine

Major congenital malformation rate AED

Very high Valproate

Intermediate Phenobarbital , Topiramate

Low to Intermediate Phenytoin, Carbamazepine

Low Oxcarbazepine , Lamotrigine, Levetiracetam

BREAST FEEDING

Barbiturate and benzodiazepines :evaluate risk /benefit

Benefit for child(decrease infection, DM, leukemia, sudden death)

for mother(ovarian and breast cancer and DM),promote mother-infant bonding

Attention to poor feeding, irritability , lethargy

children exposed to AED in utero and through breast milk have higher IQ and verbal abilities compare to who exposed in utero and not breast feed.

ROLE OF BMI

Weight gain: Valproate, Carbamazepine, Vigabatrine, Gabapantine

Weight neutral: Lamotrigine, Levetiracetam, Phenytoin

Weight loss (maybe) : Topiramate, Zonisamaide , Felbamate

ROLE OF COMORBID PSYCHIATRIC PROBLEMS

Behavioral problem

Avoid:Levetiracetam,Phenobarbital,Topiramate,Perampanel,Zonisamide,Vigabatrine

Try : Valproate, Lamotrigine, Oxcarbazepine, Carbamazepine

Mood disorderAvoid: Phenytoin, Phenobarbital, Primidone

Phenobarbital: risk of depression 40%

Try: Valproate, Lamotrigine, Carbamazepine are mood stabilizer.

ROLE OF COMORBID MEDICAL CONDITION

MigraineTopiramate, Valproate, Gabapentine , Pregabaline may be effective

PainTry Gabapentine, Pregabaline, Carbamazepine, Oxcarbazepine

ROLE OF SYSTEMIC DISEASE

Liver diseaseAvoid: Phenobarbital, Primidone, Phenytoin, Carbamazepine, Valproate,

Benzodiazepine, Felebemate, RufinamideMeasure serum drug levels , Check free level Try :Levetiracetam, Lamotrigine, Pregabaline

Renal diseaseAvoid :Gabapentin, Pregabaline, VigabatrineCaution about dialysis type ,follow serum level (e.g.: Levetiracetam, half the daily dose after HD)

CONT.

Kidney stone

Avoid: Topiramate, Zonisamide and ketogenic diet .

Potassium citrate supplement use in ketogenic diet could be effective.

ROLE OF BONE HEALTHLowering bone mineral density AED

No Lamotrigine

Maybe Topiramate, Levetiracetam

yes Carbamazepine, Oxcarbazepine, Phenobarbital,Primidone,Phenytoin,Valproate, Gabapentine,Zonisamide

No evidence of osteoporosis or osteopenia

Osteoporosis or osteopenia is detected:

Monitor Ca and vitamin D level Vit D 1500-2000 IU/day

Follow BMD every 2 year especially for postmenopausal WWE

Lifestyle modification

Ca:1200 mg/day, Vit. D:600 IU/day,Vit D level>30 ng/ml

Discuss about switching AED

Weight bearing exercise Consider bisphosphonate

Cessation of smoking Consider HRT

Limiting alcohol consumption Refer to endocrinologist

Avoiding excessive caffeine

ROLE OF DRUG-DRUG INTERACTION

Warfarin

Enzyme inducers may reduce effectiveness, like:

Phenobarbital, Phenytoin, Carbamazepine, Perampanel

Try: Levetiracetam, Lamotrigine, Lacosamide ,Pregabaline, Gabapentine

Avoid :enzyme inducer antiepileptic drugs

DRUG INTERACTION

Don’t forget enzyme induce anti epileptic drug(EIAED)which have many drug-drug interaction.

Antiseizure medication Medication with interaction

Lamotrigine Rifampin,Estrogen,Lopinavir,Ritonavir

Benzodiazepine Rifampin

Brivaracetam Rifampin

Valproate Carbapenem

Primidone Diuretic

PROCONVALSANT AND SEIZURE PROVOCATION EFFECT

Antimicrobial:

Cephepime,Ampicillin,Meropenem,Linezolide,Levofloxacin

Amphotericin

Lindan, Cloroquin

Efavirence

Antidepressant:

Bupropion,Amitriptilin,Imipiramin,Trazodone,Amoxapine,Clomipiramine

Antipsychotic

Clozapin,Clorpromazin,Hallopridole,Luxapin

CONT.Anti neoplasm:

Cyclosporine,Tacrolimus,Methotrexate,L-asparginase,Bosulfan,Blinatuzumab

Herbal medicine:

Borage, Evening primrose, Ginkgo, Ginseng, Pennyroyal, Star anise

Others:

Litium

Diphenhydramin

Tramadol

Tobacco

SKIN RASH

Consider cross-sensitivity :Carbamazepine with Oxcarbazepine, Phenytoin, Phenobarbital

Phenytoin and Zonisamide

No known specific cross sensitivity between Lamotrigine and other AED

AED with low risk of rash : Valproate,Levetiracetam,Topiramate, Gabapentine, Pregabaline

TAKE HOME MESSAGE

THANK FOR YOUR ATTENTION

Appropriate Antiseizure medication selection Outlinessystematic approachFirst step�Who needs prolonged AED administration?Slide Number 6Seizure typeSeizure freedom rate following AED administrationSlide Number 9PolytherapyRole of seizure typesRole of epilepsy typesEpileptic encephalopathyLennox- Gastaut syndromelgsrole of comorbid conditions Elderly concerns Role of sexSlide Number 19Slide Number 20Breast feeding role of BmiRole of Comorbid psychiatric problems Role of Comorbid medical condition Role of Systemic disease Cont.Role of Bone healthSlide Number 28Role of Drug-Drug interactionDrug interactionProconvalsant and seizure provocation effect�Cont.Skin rash�Take home message Thank for your attention